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Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38 - TRITON-TIMI 38
Description:
The goal of the trial was to evaluate treatment with a novel thienopyridine, prasugrel, compared with clopidogrel among patients undergoing planned percutaneous coronary intervention (PCI) for an acute coronary syndromes (ACS).
Study Design
- Blinded
- Randomized
Patients Enrolled: 13, 608
Mean Follow Up: Median 14.5 months
Mean Patient Age: Median age 61 years
Female: 26
Patient Populations:
Planned PCI for an ACS (unstable angina, or non-ST-elevation MI or ST-elevation MI); for UA/NSTEMI patients, ischemic symptoms ≥10 minutes within 72 hours of randomization, TIMI risk score ≥3 and either ST-segment deviation ≥1 mm or an elevated cardiac biomarker of necrosis for STEMI patients, symptom onset within 12 hours of randomization if primary PCI was planned, or within 14 days if medically treated for STEMI.
Exclusions:
Increased bleeding risk, anemia, thrombocytopenia, intracranial pathology, or use of any thienopyridine within 5 days.
Primary Endpoints:
Cardiovascular (CV) death, MI or stroke
Secondary Endpoints:
Primary endpoint at 30 and 90 days; stent thrombosis; CV death, MI, stroke or rehospitalization due to a cardiac ischemic event; CV death, MI, stroke or urgent target vessel revascularization (UTVR)
Drug/Procedures Used:
Patients were randomized in a double-blind manner to prasugrel (n = 6,813; 60 mg loading dose and 10 mg maintenance dose) or clopidogrel (n = 6,795; 300 mg loading dose and 75 mg maintenance dose), with study drug treatment to continue for 6 to 15 months.
Principal Findings:
The index event was unstable angina or non–ST-elevation MI in 74% of patients and ST-elevation MI in 26%. Nearly all patients underwent PCI (99%), with drug-eluting stents used in 47% of patients and bare metal stents in 47%. Approximately half of the patients in the trial were treated with a glycoprotein IIb/IIIa inhibitor (54%).
The primary endpoint of CV death, MI or stroke was significantly lower in the prasugrel group compared with the clopidogrel group (9.9% vs. 12.1%, hazard ratio [HR] 0.81, 95% CI 0.73-0.90, p < 0.001). Results were similar in the NSTEMI/UA cohort (HR 0.82, 95% CI 0.73-0.93, p = 0.002) and the STEMI cohort (HR 0.79, 95% CI 0.65-0.97, p = 0.02). The efficacy benefit was evident by 3 days (4.7% in the prasugrel group vs. 5.6% in the clopidogrel group, p = 0.01) and from 3 days to end of follow-up (5.6% in vs. 6.9%, respectively, p = 0.01). Definite or probable stent thrombosis occurred less frequently in the prasugrel group than the clopidogrel group (1.1% vs. 2.4%, HR 0.48, 95% CI 0.36-0.64, p < 0.001).
The key safety endpoint of TIMI major non-CABG bleeding was higher with prasugrel compared with clopidogrel (2.4% vs. 1.8%, HR 1.32, 95% CI 1.03-1.68, p = 0.03). The increase in bleeding was consistent for the different categories of TIMI major bleeding, including life-threatening bleeding (1.4%, vs. 0.9%, p = 0.01), both fatal (0.4% vs. 0.1%, p = 0.002) and nonfatal (1.1%, vs. 0.9%, p = 0.23). CABG-related TIMI major bleeding was also increased with prasugrel (13.4% vs. 3.2%, p < 0.001). There was no difference in mortality between the groups (3.0% in the prasugrel group vs. 3.2% in the clopidogrel group, p = 0.64).The net clinical benefit endpoint, a composite of death, MI, stroke or TIMI major bleeding, favored prasugrel (12.2% vs. 13.9%, HR 0.87, 95% CI 0.79-0.95, p = 0.004).
Interpretation:
Among patients undergoing planned PCI for an acute coronary syndromes, treatment with the novel thienopyridine, prasugrel, was associated with a reduction in the composite endpoint of CV death, MI or stroke at a median follow-up of 14.5 months compared with clopidogrel.
Patients undergoing PCI for treatment of an acute coronary syndrome are routinely treated with dual anti-platelet therapy with aspirin and clopidogrel. While a more potent platelet inhibitor can provide higher and less variable levels of platelet inhibition, it was unknown whether greater platelet inhibition would translate into improved efficacy with clinical events. The present study demonstrated that use of an agent that confers greater platelet inhibition, prasugrel, was associated with a reduction in ischemic events as compared with clopidogrel. However, as would be expected with greater platelet inhibition, there was a significant excess of bleeding events in the prasugrel group, including life-threatening and fatal bleeding. Despite this increase, the net clinical benefit endpoint, which incorporated mortality, ischemic events, and major bleeding events, favored prasugrel. Identification of subgroups at a higher risk of bleeding without improved efficacy is warranted as patients in these populations should likely not be treated with prasugrel. As noted in the manuscript, one such subgroup is patients with a history of cerebrovascular events (4% of the study), who had higher rates of bleeding without improved efficacy, and thus had a net clinical benefit in favor of clopidogrel.
References:
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
Presented by Dr. Elliott Antman at the American Heart Association Annual Scientific Session, Orlando, FL, November 2007.
Keywords: Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Pyridinolcarbamate, Drug-Eluting Stents, Thiophenes, Ticlopidine, Blood Platelets, Piperazines, Percutaneous Coronary Intervention, Metals, Thrombosis
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